Glucose elicits intrinsic and enteropancreatic reflexes; yet the mechanism by which intraluminal glucose is "sensed" and how it evokes neurally-mediated reflexes are not known. One hypothesis is that glucose activates glucoreceptors on mucosal afferent nerve fibers. Mucosal afferents are found in close proximity to epithelial cells that express glucose transporters; therefore, it is possible that after glucose is transported across the epithelium it somehow activates the processes of primary afferent neurons. We have identified enteric neurons that alter their firing rate as ambient glucose concentrations change. Glucoresponsive myenteric neurons, are depolarized by glucose, and appear to express ATP-sensitive potassium channels (KATP), that couple cell metabolism to membrane potential. We propose: (i) that basally active KATP channels contribute to the regulation of enteropancreatic reflexes; (ii) KATP channel activity is inhibited by glucose, or other nutrients, resulting in the depolarization of primary afferent neurons; (iii) depolarization opens voltage-dependent Ca2+ channels, leading to neurotransmitter release and ultimately, the activation of the enteroinsular axis. Leptin appears to act as a feedback signal informing the ENS about energy stores. The gut and the pancreas, also contain the novel hypothalamic neuropeptides called hypocretins/orexins, which increase food intake when injected into the brain. Hypocretins have so far been reported to be localized exclusively in cell bodies of the lateral hypothalamus; however, we have demonstrated that hypocretin and hypocretin receptor mRNA and protein are present in the gut and pancreas of several species, including humans. The presence of hypocretins/orexins in the gut provides further support for the idea that enteric microcircuits contribute to energy homeostasis. We will now determine whether submucosal primary afferent neurons are glucoresponsive and "sense" intraluminal glucose and whether the mechanism of excitation by mucosal glucose involves KATP channels. We will determine whether enteric KATP channels are abnormal in KATP channel-deficient (SUR1-/-) mice, and whether this leads to abnormal glucose-induced reflexes. We will determine whether ambient leptin levels modulate the activity and secretion of enteric glucose "sensing" cells, and whether this is due to alteration of KATP channel activity. We also propose to define the role played by hypocretins in the gut and pancreas, and whether the expression of hypocretins in the bowel is linked to nutritional state.